Potts, W. K. | Search bioRxiv

bioRxiv2025

Influenza virus evolution and defective genome formation are shaped by host genotype and sex

Viral evolution during initial pandemic waves favors mutations that enhance replication and transmission over antigenic escape. Host genotype and sex strongly shape this early adaptation, yet their individual and combined effects remain unclear. We experimentally adapted influenza A virus to male and female BALB/c and C57BL/6 mice, generating 28 independent lineages, and employed a novel "rolling sphere" approach to identify mutational hotspots in three-dimensional protein structures. In BALB/c mice, adaptation favored nonsynonymous substitutions linked to increased virulence, including a hemagglutinin variant exclusively fixed in female lineages. It also revealed the first demonstration of sex-dependent selection shaping a viral protein interface. In female-adapted viruses, substitutions disrupting a key NS1 dimerization motif converged on a single residue, while in male-adapted viruses, they were dispersed across the same interface. Conversely, adaptation to C57BL/6 resulted in fewer substitutions but promoted defective viral genome formation, leading to reduced cytopathic effect and attenuated virulence. This provides the first in vivo evidence that host genotype alone can modulate defective viral genome formation. Our results offer critical insights into host-pathogen interactions and reveal that selective pressures imposed by specific genotype-sex combinations can increase virulence across host genotypes, enabling new epidemiological modeling and disease control strategies.

evolutionary biology↗

bioRxiv2018

Transitions in paternal dominance regulate offspring growth and metabolic transcription

Parental effects are an important source of adaptive traits. By contrast, parental effects failing to regulate offspring phenotype to fit current conditions could be deleterious. Although adaptive parental responses to single cues have been identified, we lack an understanding of the reversibility of parental effects across breeding cycles in a fluctuating environment. Social status of parents can occasionally fluctuate and, in turn, influence high-fitness pathways available to offspring. We show that social competition status results in robust parental effects on growth in mice. Dominant males produce faster growing offspring because of status related cues, not genetic associations. The timing, effect-size, and sex-specificity of this paternal effect are modulated by maternal experience. We experimentally demonstrate that status-ascending males produce heavier sons than before, and status-descending males produce lighter sons than before. Paternal status predicts genome-wide transcription in the liver, including transcriptional networks controlling xenobiotic and fatty acid metabolism, and oxidative phosphorylation. Our study demonstrates that paternal social status reversibly conditions offspring growth in naturalistic environments.

evolutionary biology↗